Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study

Follicular lymphoma (FL) is a common indolent non-Hodgkin lymphoma (iNHL), with first-line treatment typically involving immunochemotherapy. While rituximab improved outcomes, patients with progression of disease within 24 months (POD24) from first-line therapy or those double-refractory to CD20-targeting agents and alkylating agents have poor prognoses and limited treatment options. CAR T-cell therapy offers promise, but its optimal timing and efficacy in high-risk second-line (2L) FL are unclear. This study investigates lisocabtagene maraleucel (liso-cel), a CD19-directed CAR T-cell product, in R/R FL patients, focusing on high-risk 2L patients. The study aims to assess the efficacy and safety of liso-cel across various lines of therapy, particularly in this challenging population where there is a lack of standard treatment and patients face poor outcomes.

The literature highlights the need for improved treatments for patients with relapsed/refractory follicular lymphoma, particularly those exhibiting high-risk features such as POD24 or double refractoriness. While immunochemotherapy with rituximab has improved overall survival, a significant portion of patients still experience relapse or refractoriness. CAR T-cell therapies have shown promise in later-line settings but data on their application in high-risk second-line patients remain limited. Previous studies of liso-cel in other lymphoma subtypes indicated its potential efficacy and safety profile.

TRANSCEND FL (NCT04245839) is a global, phase 2, open-label, single-arm, multi-cohort, multicenter study. It enrolled adult patients (≥18 years) with histologically confirmed FL who received at least one prior line of systemic therapy with an anti-CD20 antibody and alkylator. Patients were categorized into cohorts based on lines of prior therapy (2L, 3L+). The 2L cohort included high-risk patients with POD24 and/or meeting modified Groupe d’Etude des Lymphomes Folliculaires (mGELF) criteria. Leukapheresis was performed for liso-cel manufacturing. Treatment involved lymphodepleting chemotherapy (LDC) followed by liso-cel infusion. Optional bridging therapy was permitted during liso-cel manufacturing. The primary endpoint was ORR per an independent review committee (IRC) using PET/CT. Secondary endpoints included CR rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, cellular kinetics, and patient-reported outcomes (PROs). Statistical analyses included exact binomial tests, Kaplan-Meier methods, and analyses of patient-reported outcomes using the EORTC QLQ-C30 and FACT-LymS questionnaires. Hierarchical hypothesis testing was used to control for type I error.

A total of 130 patients received liso-cel (median follow-up: 18.9 months). In the 101 patients with third-line or later FL, the ORR was 97% (95% CI: 91.6–99.4), and the CR rate was 94% (95% CI: 87.5–97.8). In the 23 patients with 2L FL, the ORR was 96% (95% CI: 78.1–99.9), with all responders achieving CR. Responses were rapid (median time to response: 1 month) and durable (median DOR not reached at median follow-up of ~17 months). 12-month DOR and PFS rates were high across all subgroups, including those with high-risk disease features. Cytokine release syndrome (CRS) occurred in 58% of patients (grade ≥3 in 1%), and neurological events occurred in 15% (grade ≥3 in 2%). Cellular kinetic analyses showed rapid liso-cel expansion and persistence. Patient-reported outcomes demonstrated improvement in quality of life, symptoms, and functioning after liso-cel infusion.

TRANSCEND FL provides the largest clinical trial dataset on CAR T-cell therapy in R/R FL to date, including the first report of its use in high-risk 2L FL patients. The high ORR and CR rates observed with liso-cel across various lines of therapy, particularly in the high-risk 2L cohort, demonstrate its significant therapeutic potential. The durable responses and manageable toxicity profile further support its clinical benefit. While direct comparisons across different CAR T-cell therapies are limited by variations in study design and definitions, the results suggest comparable or superior efficacy to other approved therapies for R/R FL. The observed high response rates might limit subgroup comparisons, but the study's results indicate the potential for sustained responses and survival in patients across subgroups regardless of risk factors. The improvement in patient-reported outcomes further underscores the overall clinical benefit and quality of life improvements.

Lisocabtagene maraleucel demonstrates high efficacy and a manageable safety profile in patients with R/R FL, including those with high-risk 2L disease. The results support liso-cel as a valuable therapeutic option for this challenging patient population. Further studies with longer follow-up are needed to fully assess long-term outcomes and to better understand the impact of cellular kinetics on efficacy and safety. Future research could also explore the potential for combining liso-cel with other therapies to improve outcomes further.

The single-arm design limits direct comparison to other treatments, and longer follow-up is needed for DOR and PFS. The number of patients in the outpatient monitoring group was affected by regulatory requirements and the COVID-19 pandemic. The relatively young age of the study population might limit generalizability to older individuals.